RMD Open最新文献

Introduction: Familial Mediterranean fever (FMF) is a genetic disease leading to recurrent episodes of inflammation. Two pathogenic variants are required for classical disease, but the disease can occur in heterozygous patients. Patients are treated continuously with colchicine to prevent amyloid A (AA) amyloidosis, including heterozygous patients who display a moderate form of FMF and rarely develop AA amyloidosis. The need for lifelong colchicine treatment in heterozygous FMF is therefore controversial. We aimed to characterise genotype-specific levels of inflammatory biomarkers, and to focus on heterozygous patients who discontinued colchicine.

Methods: All patients with FMF from the European databases AIDnet and JIRcohort who received colchicine during follow-up were included. Demographics, C reactive protein (CRP), serum amyloid A (SAA), S100A8/A9 and S100A12 levels, leucocyte and neutrophil counts were extracted. Visits were classified as active, subclinical or inactive according to symptoms, CRP and SAA levels.

Results: Data from 747 patients were extracted (233 homozygous, 201 compound heterozygous, 224 heterozygous patients, 49 heterozygous with one class III variant and 40 compound heterozygous with two class III variants). During active visits, all biomarker levels were higher compared with inactive visits (p<0.001). Heterozygous patients showed lower levels of CRP, SAA, S100A8/A9 and S100A12 during inactive and subclinical visits than patients with two class IV-V variants. Colchicine was discontinued in 52 heterozygous patients and reintroduced in 23 of them (44%).

Conclusion: S100A8/A9 and S100A12 proteins are biomarkers that can be used to assess disease activity. Heterozygous patients have lower levels of inflammatory biomarkers and some of them can sustainably discontinue colchicine treatment.

Objectives: The Newcastle Sjogren's Stratification Tool (NSST) stratifies Sjogren's disease patients into four subtypes. Understanding the stability of the subtypes is vital if symptom-based stratification is to be more broadly adopted. In this study, we stratify patients longitudinally to understand how symptom-based subtypes vary over time and factors influencing subtype change.

Methods: 274 patients from the United Kingdom Primary Sjögren's Syndrome Registry (UKPSSR) with data permitting NSST subtype assignment from two study visits were included. The French Assessment of Systemic Signs and Evolution of Sjogren's Syndrome (ASSESS) cohort (n=237) acted as an independent comparator. Group analyses of significant differences were performed, with logistic regression models used to assess covariates of subtype stability.

Results: UKPSSR and ASSESS cohorts showed a broadly similar proportion of subjects in each subtype and similar baseline clinical characteristics except body mass index (BMI). Several baseline characteristics differ significantly between the subtypes, most notably anti-Ro status and BMI. Subtype membership was reasonably stable in both cohorts with 60% and 57% retaining subtype. The high-symptom burden subtype was the most stable over time with 70% and 67% retaining subtype. Higher baseline probability score was the greatest predictor of subtype stability with higher C4 levels, antidepressant use, and a higher CCI score also predicting increased stability.

Conclusion: NSST subtype membership remains stable over time in a large proportion of patients. When subtype transition is associated with factors at baseline, it is most strongly associated with an uncertain subtype allocation. Our findings support the hypothesis that symptom-based subtypes reflect genuine pathobiological endotypes and therefore maybe important to consider in trial design and clinical management.

Objectives: The determinants of rheumatoid arthritis (RA) severity and excess cardiovascular disease (CVD) are incompletely understood. Biomechanical factors are known to influence RA severity. Articular stiffness correlates with arterial and skin stiffness. This study explored the hypothesis that constitutional stiffness is a common determinant of RA severity and excess CVD.

Methods: Fifty-eight patients with anti-CCP antibody (ACPA) positive RA and 57 controls were enrolled noting age, sex, body mass index, alcohol and tobacco exposure, Shared Epitope status and in RA disease duration, disease activity, ACPA titre and radiographic damage. Severe RA was defined as radiographic progression >1.3 mSharp points/year or requiring biological disease-modifying antirheumatic drugs (bDMARDs). Articular stiffness (Beighton Score and right 5th metacarpophalangeal (MCP) joint stress-strain responses), carotid-femoral pulse wave velocity and skin extensibility (percent increase distance two dots with manual traction dorsum right hand) were assessed.

Results: Right 5th MCP stiffness correlated with Beighton Score and with arterial and skin stiffness. High radiographic rate was associated with greater MCP articular (t test p 0.014), arterial (p 0.044) and, in RA <5 years duration, greater skin stiffness (p 0.002) with similar trends in subjects requiring bDMARDs. In RA, arterial stiffness correlated with age (ß p<0.005), articular (ß p<0.001) and skin stiffness (ß p 0.037) and inversely with alcohol consumption (p 0.035).

Conclusions: Articular, arterial and skin stiffness correlated with each other and with RA severity. As skin is not affected by RA, this association suggests that constitutional stiffness might be a common determinant of RA and CVD. Prospective studies of at-risk preclinical and early RA are required to determine if this relationship is causal.

Trials registration number: ACTRN12617000170325.

Objective: The 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria score (≥20 points) has been associated with poor outcomes. We aimed to evaluate its utility as a predictor for mortality and hospitalisation and to derive and validate an ominosity score based on the SLE classification criteria set.

Methods: Incident patients with SLE in a population-based cohort were included. The association between the 2019 EULAR/ACR SLE score and mortality and hospitalisation was assessed using Cox regression adjusted for age, sex and calendar year. An ominosity score for mortality was developed based on the SLE criteria set. The least absolute shrinkage and selection operator method was used to estimate model coefficients. Concordance and calibration were assessed by cross-validation and by plotting the observed event rates against the deciles of predicted probabilities.

Results: Among 374 patients with incident SLE, a EULAR/ACR score ≥20 points was not associated with an increased risk of mortality (HR 1.17, 95% CI 0.67 to 2.03) or first hospitalisation (HR 1.14, 95% CI 0.79 to 1.64) compared with a score ≤19 points. The derived ominosity score for mortality included age, sex, thrombocytopaenia, neuropsychiatric manifestations, subacute cutaneous or discoid lupus, non-scarring alopecia, inflammatory arthritis, renal involvement, antiphospholipid antibodies and hypocomplementaemia. This model demonstrated a concordance=0.76 with adequate calibration. Age and sex were the main predictors, as seen in the model including just age, sex and year (concordance=0.77).

Conclusion: The 2019 EULAR/ACR SLE criteria score was not associated with mortality and hospitalisation. The derived ominosity score for mortality presented good prediction for mortality but was not better than age and sex alone.

Introduction: Systemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc.

Methods: Data for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality.

Results: We included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection.

Conclusion: This study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients' classification based on only skin extension is not sufficient for defining prognosis and phenotype.

Objectives: The aim of this study was to combine deep T cell phenotyping with assessment of citrulline-reactive CD4+T cells in the pre-rheumatoid arthritis (RA) phase.

Methods: 20 anti-CCP2 positive individuals (HLA-DRB1*04:01) presenting musculoskeletal complaints without clinical or ultrasound signs of synovitis; 10 arthritis progressors and 10 matched non-arthritis progressors were included. Longitudinal samples (1-3 time points) of peripheral blood mononuclear cells were assessed using HLA-class II tetramers with 12 different citrullinated candidate autoantigens combined in a >20-colour spectral flow cytometry panel.

Results: The baseline CD4+T cell phenotype was similar between individuals who progressed to arthritis (ie, in the pre-RA phase) and the non-progressors, when studying markers associated with Th1, Th17, T-peripheral and T-regulatory cells as well as with T-cell activation. Citrulline-reactive CD4+T cells were present in both groups but at significantly lower frequency in the progressor group. CD4+T cells specific for citrullinated tenascin-C were the most frequently observed among the progressors, and their frequencies diminished during follow-up that is, closer to arthritis onset. Notably, PD-1 and CD95 expression on the memory cit-tenascin-C-specific T cells in this group indicated repeated antigen exposure.

Conclusions: Our data lend support to citrullinated tenascin-C as an interesting T cell antigen in RA. Moreover, lower frequency of circulating citrulline-specific cells in arthritis progressing individuals suggest an initiated homing of these cells to the joints and/or their associated lymph nodes in the pre-RA phase and a possible window of opportunity for therapeutic preventive interventions.

Objectives: In systemic sclerosis (SSc), gastrointestinal involvement is one of the earliest events. We compared the gut microbiota (GM), its short-chain fatty acids (SCFAs) and host-derived free fatty acids (FFAs) in patients with very early diagnosis of SSc (VEDOSS) and definite SSc.

Methods: Stool samples of 26 patients with SSc, 18 patients with VEDOSS and 20 healthy controls (HC) were collected. The GM was assessed through 16S rRNA sequencing, while SCFAs and FFAs were assessed by gas chromatography-mass spectrometry.

Results: In patients with VEDOSS, an increase in Bacteroidales and Oscillospirales orders and a decrease in Bacilli class, Blautia, Romboutsia, Streptococcus and Turicibacter genera was detected in comparison with HC. In patients with SSc, an elevated number of Acidaminococcaceae and Sutterellaceae families, along with a decrease of the Peptostreptococcaceae family and Anaerostipes, Blautia, Romboutsia and Turicibacter genera was found in comparison with HC. Patients with SSc and VEDOSS had a significantly lower butyrate and higher acetate with respect to HC. In VEDOSS, an increase in Oscillospiraceae family and Anaerostipes genus, and a decrease in Alphaproteobacteria class, and Lactobacillales order was identified with respect to SSc. Moreover, patients with VEDOSS exhibited higher acetate and lower valerate compared with definite SSc.

Conclusion: A GM dysbiosis with depletion of beneficial anti-inflammatory bacteria (especially butyrate-producing) and a significant decrease in faecal butyrate was identified in patients with VEDOSS. This early GM imbalance may foster the growth of inflammatory microbes, worsening intestinal dysbiosis and inflammation in early SSc stages. The potential butyrate administration in early disease phases might be considered as a novel therapeutic approach to mitigate gastrointestinal discomfort and progression preserving patient's quality of life.

Objective: To discover antibody biomarkers that can predict a lack of response to first-line therapy in rheumatoid arthritis (RA) patients.

Methods: Two RA cDNA phage display libraries were screened for novel antibodies in baseline RA sera from the Care in early RA (CareRA) trial, differentiating between patients who did or did not reach remission after first-line therapy (n=20 each). Antibody reactivity to identified University Hasselt (UH)-RA antigens was validated in baseline samples from 136 additional CareRA participants. The novel antibodies' potential to predict failure to reach remission or low disease activity (LDA), according to the Disease Activity Score 28-joint C-reactive protein/erythrocyte sedimentation rate (DAS28CRP/ESR) and Clinical/Simplified Disease Activity Index (CDAI/SDAI), was studied by multivariate analyses. The presence of the antibody targets in RA synovial tissue and the fibroblast-like synoviocyte (FLS) cell line SW982 was determined by immunofluorescence.

Results: We identified antibodies to 41 novel antigens. Antibodies against any of three antigens, UH-RA.305/318/329, discriminated between RA patients not reaching week (w)8 DAS28CRP remission and those that did (36% vs 13%,p=0.0031). In all patients, anti-UH-RA.305/318/329 antibody reactivity was associated with failure to reach week 8 DAS28CRP and DAS28ESR remission (OR 3.63,p=0.0031; OR 2.92,p=0.016; respectively), SDAI/CDAI sustained remission (OR 5.59,p=0.039 for both) and DAS28CRP and DAS28ESR sustained LDA (OR 3.7,p=0.009; OR 2.76,p=0.042; respectively). In rheumatoid factor/anti-citrullinated protein antibody (RF/ACPA) seronegative patients, these antibodies were strongly associated with failure to achieve week 8 DAS28CRP remission (OR 17.3,p=0.0029). Anti-UH-RA.305/329 antibodies were shown to target FLS in RA synovial tissue and SW982 cells.

Conclusion: We identified three antibody biomarkers that are associated with failure to achieve remission/LDA after first-line RA therapy.

Objectives: The objectives of this study are to identify a therapeutic serum level for adalimumab associated with remission and low disease activity in patients with rheumatoid arthritis.

Methods: Associations between serum adalimumab trough levels and disease activity were examined using longitudinal data from a 48-week randomised phase III trial including patients with tumour necrosis factor inhibitor-naïve rheumatoid arthritis with active disease starting adalimumab treatment. Disease activity was classified according to 28-joint Disease Activity Score (DAS28)-erythrocyte sedimentation rate and C reactive protein (CRP) levels.

Results: Adalimumab trough levels were recorded longitudinally for 336, 330 and 302 patients at weeks 12, 24 and 48, respectively. All patients received concomitant methotrexate. Median adalimumab trough levels were 6.4 mg/L (IQR 3.4-9.5) at week 12, 7.5 mg/L (IQR 3.5-10.9) at week 24 and 7.6 mg/L (IQR 3.6-12.0) at week 48. In serial serum samples from weeks 12, 24 and 48, trough levels ≥3.9 mg/L were associated with DAS28 remission (OR 3.88 (95% CI 1.80, 8.38), p<0.001) and lower CRP levels (p<0.001). Week 12 trough levels ≥3.5 mg/L were associated with DAS28 low disease activity at week 24 (OR 2.62 (1.50, 4.56), p<0.001) and remission at week 48 (OR 1.99 (1.02, 3.88), p=0.04), as well as lower CRP levels at both time points (p<0.001).

Conclusion: Adalimumab trough levels above 4.0 mg/L were associated with remission/low disease activity throughout the first year of adalimumab therapy and can be considered a lower target level for therapeutic drug monitoring of adalimumab therapy.